The use of tablets is a common method of administration of therapeutic substances in solid form. Such substances may include, for instance, medications and dietary supplements. There are several advantages to tableting. Tablets reduce bulk, making swallowing easier, and provide an alternative to liquid solutions or suspensions. Coated tablets help to preserve the table contents and also reduce or mask unpleasant taste and/or odor.
A number of problems can present themselves in therapeutic systems which use low density substances, substances which are chemically unstable and/or substances having unpleasant taste or odors. One example of such a system is that used in the treatment of chronic renal failure. These systems generally comprise a combination of amino acids and keto- and hydroxy-analogues thereof. Examples of these systems are described in U.S. Patents to Walser U.S. Pat. Nos. 4,228,099; 4,296,127; 4,320,146; and 4,352,814; U.S. Pat. No. 4,908,214 to Bobee, et al.; U.S. Pat. No. 4,957,938 to Anderson, et al.; and European Patent application No. 0 184 999 to Iaccherl, all of which are hereby incorporated herein by reference. A major problem associated with these systems is that the component materials have low bulk density and must be consumed at relatively high daily dosages. Another problem attendant to these systems is that many of the components present organoleptic concerns (i.e. those related to the taste, smell, appearance, mouthfeel, etc.). For example, ornithine .alpha.-ketoisocaproate, lysine .alpha.-keto-.beta.-methylvalerate, histidine .alpha.-ketoisocaproate, tryptophan, and calcium .alpha.-hydroxy-.gamma.-methylthiobutyrate are extremely bitter. Also, volatile decomposition products of the components, such as isovaleric acid, methylbutyric acid, and isobutyric acid, have very unpleasant odors. Other components, such as tyrosine, have a gritty mouth feel. These problems of sensory acceptance make oral administration of such untableted systems very unpalatable for the patients.
Presently these problems are addressed by the oral administration of solvated or suspended powders in highly flavored liquids. This technique deals with the low bulk density by presenting the therapeutic substance in liquid form while the flavoring masks the unpleasant taste and odor. However, some of the problems associated with this method are the unacceptability of the liquid to a segment of the population, and the complexity and expense of manufacturing, packaging and transporting a liquid formulation. Also, the formulation often must be wholly or partially reconstituted which can complicate administration, particularly in systems requiring high daily dosages. In addition, the presence of the flavoring agents has the potential for degradation of the active components when in aqueous solution or suspension.
Another alternative presently used is the production of tablets using a wet granulation process. This known process eliminates the problems of low bulk density and air entrapment. This process involves the use of a solution or binder added to the dry powder accompanied by some type of physical mixing action. In this method, the binder solution is intended to wet the surface of the powder particles or crystals, thereby displacing air which is present in the pores and interstices. This method often provides some dissolution of the powdered substance by the binder solution, which assists in densifying the material when the compaction and subsequent drying processes are complete. Wet granulation can be carried out using either aqueous or alcohol-based binder solutions. Although the wet granulation method has been successful in many applications, some potential problems remain. The binder solution will solvate some of the powder components which can accelerate degradation reactions. Once the wet-granulated powder is compressed into tablet form, small amounts of remaining solvent will accelerate degradation of the components.
Another approach to the densification of powdered substances has been that of "slugging" the material. "Slugging" comprises compressing large tablets of the material on a tableting machine. This process requires that the powdered substance have suitable flow characteristics and be amenable to compression so as to form a compacted material which survives ejection from the tablet die. Many powder materials, such as those used in the treatment of chronic renal failure discussed above, do not compress well enough to form a sufficiently strong compact to survive ejection from the tablet die, even at extremely low speeds. Other components, while moderately compressible and capable of forming a compact, require slow ejection from the die in order to maintain a compacted state. Accordingly, slugging is not feasible for renal systems.
There are other problems that specifically relate to the tableting formulations used in the treatment of chronic renal failure. Since these materials are nutritional agents (or their biochemical precursors) rather than typical pharmaceutical agents, a large amount of the powder blend must be consumed. For example, a typical patient may have to consume a daily dosage of 25 grams to receive the therapeutic benefits and avoid negative nitrogen balance. It is well known in the area of pharmaceuticals that many patients, particularly pediatric and geriatric patients, have a difficult time swallowing either large tablets or large numbers of tablets. Some of this difficulty may be mechanical (e.g. esophageal stricture, insufficient saliva, esophageal spasm due to gag reflexes), but it may also have a significant psychological component. The patients may come to dread swallowing large tablets which cause discomfort or a choking sensation.
It is well known that tableting excipients can be effective in improving compressibility and compactability of powders. In some systems, it may be possible to add large quantities of these excipients (e.g. microcrystalline cellulose, lactose, compressible sugar, dicalcium phosphate, and the like) to the powder blend, and directly improve the tableting characteristics of the material. However, this would necessitate making the tablets much larger or requiring the patients to consume many more tablets. Both of these alternatives are undesirable or unacceptable from the point of view of compliance.
In view of the foregoing problems existing in the prior art, and the desired objectives and advantages to be achieved in a tableted substance, the medical community has long sought a tablet which is chemically stable, is of a size which can be easily swallowed, and does not have an offensive taste or odor.